bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–07–06
ten papers selected by
Verena Kohler, Umeå University



  1. MedComm (2020). 2025 Jul;6(7): e70259
      As fundamental units of life activities, cells exhibit a high degree of structural refinement and functional specialization, forming the cornerstone of life complexity. Compartmentalization within cells is pivotal for maintaining the orderly progression of intracellular biochemical processes. Cellular compartments constitute the enclosed regions within the cytoplasm of all eukaryotic cells and are typically surrounded by a single or double layer of phospholipids, and include major organelles, such as the endoplasmic reticulum (ER) and mitochondria. Compartmentalization enables organelles to maintain distinct environments in terms of space, physics, and chemistry, thereby increasing their functionality. Human health is closely associated with cellular organelle homeostasis, and organelle dysfunction affects disease pathogenesis. In contrast to isolated cellular compartments, organelles are interdependent and communicate via membrane contact sites, with close membrane contact between the ER and mitochondria, forming mitochondria-associated ER membranes (MAMs), which are involved in multiple cellular functions and whose integrity and function are essential for cellular homeostasis, with dysfunction implicated in various diseases. Investigating MAMs structure, function, and disease-state alterations informs mechanisms and developing therapies. This article reviews the discovery, structure, function, and research progress of MAMs in human systemic diseases and cancer and explores their potential as therapeutic targets.
    Keywords:  endoplasmic reticulum; human diseases; mitochondria; mitochondria‐associated endoplasmic reticulum membranes
    DOI:  https://doi.org/10.1002/mco2.70259
  2. Mol Biol Cell. 2025 Jul 02. mbcE25020089
      Membrane contact sites are regions where organelle membranes come together, and serve as platforms for metabolite exchange, process organization, and regulation of organelle dynamics. The yeast vacuole, equivalent to lysosomes in higher eukaryotes, functions as a degradative organelle, storage compartment, and signaling hub, establishing contacts with multiple organelles. We previously identified the protein Cvm1 as a component of vacuole contact sites with mitochondria, the nuclear endoplasmic reticulum, and peroxisomes. Here, we investigate Cvm1-mediated contacts and show that the contacts with mitochondria require the porins Por1 and Por2. Additionally, Cvm1 forms a protein complex with its paralog Yml020w, which we designate as Cvm2. Bioinformatic analysis predicts that both proteins contain an α/β-hydrolase fold. Notably, the predicted catalytic triad of Cvm2 is essential for its in vivo function, while Cvm1 lacks an active site. Complex formation is necessary for the function of the proteins, and Cvm1 targets the complex to the vacuole by binding phosphatidylinositol-3-phosphate on this membrane. Overexpression of this complex generates extended contacts between the vacuole and the peripheral endoplasmic reticulum. Collectively, our work describes the novel Cvm1-Cvm2 complex and molecular interactions important for its function as part of vacuolar contact sites. [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-02-0089
  3. Pharmacol Biochem Behav. 2025 Jul 02. pii: S0091-3057(25)00104-2. [Epub ahead of print] 174057
      Chronic stress has been widely reported to be related to alterations in emotional behaviors of individuals, yet the potential effects of post-weaning stress (PWS) and the associated mechanisms are still poorly understood. Mitochondria-associated endoplasmic reticulum membranes (MAM) play crucial roles in cellular energy metabolism, calcium homeostasis, lipid synthesis, and have been highlighted in recent studies for their importance in the nervous system. This study aims to explore how PWS affects behaviors, especially aggressive behavior and social hierarchy, and whether MAM plays a role in this process in ICR mice. Various behavioral assessments were employed to measure different behaviors: the open field test (OFT) and elevated plus maze (EPM) for anxiety-like behavior, the resident-intruder test (RIT) and defensive aggression test (DAT) for aggressive behavior, and the social dominance test (SDT) to evaluate social hierarchy. Transmission electron microscopy and Immunofluorescence staining were used to analyze the MAM structure in the neurons of hypothalamus, a crucial brain region that regulates the various behaviors described above. The findings indicated that PWS reduced weight gain and elevated social hierarchy in male mice. Behavioral effects were assay-specific: aggression decreased in the resident-intruder test (attack frequency/time) but not the defensive aggression test, while anxiety-like behaviors showed mixed results (increased open-arm exploration in EPM but no OFT changes). Females exhibited reduced locomotion without aggression or anxiety alterations. Notably, a decrease in mitochondrial-endoplasmic reticulum contact was observed, accompanied by decreased voltage-dependent anion channel (VDAC1) in males and increased Inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in females. These alterations may influence energy metabolism and stress responses, potentially contributing to the observed behavioral changes. These findings emphasize the importance of understanding the neurobiological underpinnings of aggression and stress response, particularly in relation to stress experienced during early life.
    Keywords:  Aggressive behavior; Hypothalamus; Mitochondria-associated endoplasmic reticulum membrane; Post-weaning stress; Social behavior
    DOI:  https://doi.org/10.1016/j.pbb.2025.174057
  4. Aging Cell. 2025 Jun 30. e70137
      Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres, forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice, we reveal that aging slows muscle relaxation, leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We also demonstrate that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are affected early in aging and are closely associated with the rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca2+ homeostasis, cytoskeleton integrity, and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.
    Keywords:  aging; endoplasmic reticulum; exercise; mitochondria; mitochondrial‐associated ER membranes; sarcopenia; sarcoplasmic reticulum; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.70137
  5. Alzheimers Res Ther. 2025 Jul 04. 17(1): 148
       BACKGROUND: Alzheimer's disease (AD) is the major age-related form of dementia in which dysfunctional ubiquitin-proteasome system (UPS) and autophagy represent primary mechanisms leading to accumulation of misfolded proteins, dysfunction of astroglial cells, neuroinflammation and neurodegeneration. Alterations of the endoplasmic reticulum (ER)-mitochondria contact sites (MERCS), specifically the shortening of the distance between the organelles, was proposed as a key mechanism of cell dysfunction in AD. However, its link to the impairment of the proteolytic system in AD remains unexplored.
    METHODS: We used, as a model, hippocampal astrocytes from 3xTg-AD mice expressing either control plasmid or synthetic linkers stabilizing ER-mitochondrial interaction at 10 nm (10 nm-EML) or at 20 nm (20 nm-EML). Alternatively, astrocytes were treated with mitochondrial Ca2+ uptake inhibitor benzethonium chloride or activator amorolfine. We used Western blot to assess protein expression and specific enzymatic activity tests for the analysis of proteasomal, autophagic and lysosomal activities. Single cell fluorescent Ca2+ imaging, using 4mtD3cpv probe targeted to the mitochondrial matrix, was used to assess mitochondrial Ca2+ uptake.
    RESULTS: Stabilization of MERCS at 20 nm (20 nm-MERCS), which promotes mitochondrial Ca2+ uptake, rescued protein ubiquitination, UPS composition and activity. Immunoproteasome components β2i and β5i, upregulated in AD astrocytes, and INFγ, a master-regulator of UPS remodelling in inflammatory conditions, were also rescued. Autophagic markers beclin 1, LC3II and p62, and lysosome-related marker cathepsin B, all upregulated in AD astrocytes, were significantly reduced, while autophagic flux was rescued, by stabilizing 20 nm-MERCS. Furthermore, stabilization of 20 nm-MERCS fully rescued previously reported deficit of mitochondrial Ca2+ uptake. Strikingly, application of a mitochondrial Ca2+ uptake positive modulator, amorolfine, partially rescued pathological remodelling of UPS and autophagy, suggesting that both mitochondrial Ca2+-related and Ca2+-unrelated mechanisms play a role in the beneficial effect of 20 nm-MERCS stabilization on protein dyshomeostasis.
    CONCLUSIONS: Our results suggest that disruption of ER-mitochondrial interaction is a key factor for AD-related dysregulation of protein degradation and provide a proof that stabilization of MERCS at a defined distance and/or pharmacological rescue of mitochondrial Ca2+ uptake represent valuable strategies for the development of future anti-AD therapy.
    Keywords:  Alzheimer’s disease; Amorolfine; Astrocytes; Autophagy; ER-mitochondrial contact sites; ER-mitochondrial distance; Immunoproteasome; Lysosomal degradation; Mitochondrial calcium uptake; Proteasome
    DOI:  https://doi.org/10.1186/s13195-025-01793-9
  6. Trends Biotechnol. 2025 Jul 01. pii: S0167-7799(25)00217-3. [Epub ahead of print]
      In cancer cells, lipid droplets (LDs) establish extensive membrane contact sites (MCSs) with mitochondria to facilitate fatty acid transfer and sustain energy production, thus enabling cancer cell survival, in nutrient-deprived tumor microenvironments. However, effective strategies to disrupt these LD-mitochondria interactions remain unavailable. We engineered an optogenetic system to control LD intracellular organization through clustering. Upon blue light stimulation, the system induces LDs to undergo spatial reorganization and form clusters, thereby restricting LD accessibility by reducing the available surface area for mitochondrial interaction. Consequently, this clustering significantly diminishes the number of LD-mitochondria MCSs, suppresses fatty acid transport from LDs to mitochondria during starvation, and ultimately leads to cancer cell death in vitro and tumor growth inhibition in vivo. Collectively, our results demonstrate that optogenetically controlled LD clustering offers a novel approach to impede tumor progression by blocking nutrient flow from LDs to mitochondria.
    Keywords:  cancer therapy; lipid droplets; membrane contact sites; optogenetics; organelles
    DOI:  https://doi.org/10.1016/j.tibtech.2025.06.002
  7. Circulation. 2025 Jun 30.
       BACKGROUND: Pathological cardiac remodeling after myocardial infarction (MI) is a leading cause of heart failure and sudden death. The detailed mechanisms underlying the transition to heart failure after MI are not fully understood. Disruptions in the endoplasmic reticulum (ER)-mitochondria connectivity, along with mitochondrial dysfunction, are substantial contributors to this remodeling process. In this study, we aimed to explore the impact of mitochondrial tumor suppressor 1A (Mtus1A) on cardiac remodeling subsequent to MI and elucidate its regulatory role in ER-mitochondria interactions.
    METHODS: Single-nucleus RNA sequencing analysis was performed to delineate the expression patterns of Mtus1 in human cardiomyocytes under ischemic stress. MI models were induced in mice by left coronary artery ligation and replicated in vitro using primary neonatal rat ventricular myocytes exposed to oxygen glucose deprivation. Cardiac-specific deletion of Mtus1 was achieved by crossing floxed Mtus1 mice with the Myh6-MerCreMer mice. The impact of Mtus1A, a mitochondrial isoform of Mtus1, on cardiac function and the molecular mechanisms were investigated in both in vivo and in vitro settings. Mitochondria-associated ER membranes coupling levels were evaluated by transmission electron microscopy and live-cell imaging. Protein interactions involving Mtus1A were explored through immunoprecipitation-mass spectrometry, coimmunoprecipitation, and proximity ligation assay. The roles of Mtus1A and Fbxo7 (F-box protein 7) were validated in a murine MI model using adeno-associated virus serotype 9 (AAV9).
    RESULTS: Bioinformatics analysis revealed a significant downregulation of Mtus1 expression in human cardiomyocytes under ischemic conditions, indicating its potential role in stress response. The predominant isoform in murine cardiomyocytes, Mtus1A, showed reduced expression in the left ventricle of mice after MI, which is consistent with the decreased levels of its orthologs in heart tissues from patients with MI. Cardiac-specific knockout of Mtus1 in mice exacerbated cardiac dysfunction after MI. Both in vitro and in vivo studies demonstrated the vital role of Mtus1A in modulating mitochondria-associated ER membranes coupling and preserving mitochondrial function. Mechanistically, Mtus1A functions as a scaffold protein that maintains the formation of inositol 1,4,5-trisphosphate receptor 1 (IP3R1)-glucose-regulated protein 75 (Grp75)-voltage-dependent anion channel 1 (VDAC1) complex through its amino acid sequence 189-219. In addition, Mtus1A protein is stabilized by K6-linked ubiquitination through the E3 ubiquitin ligase Fbxo7. Mtus1A overexpression in mice mitigated MI-induced cardiac dysfunction and remodeling by maintaining ER-mitochondria connectivity.
    CONCLUSIONS: Our study demonstrates that Mtus1A is crucial for modulating MI-induced cardiac remodeling by preserving ER-mitochondria communication and ameliorating mitochondrial function in cardiomyocytes. Mtus1A may serve as a potential therapeutic target for treating heart failure after MI.
    Keywords:  Mtus1A; mitochondria-associated endoplasmic reticulum membranes; myocardial infarction; ubiquitination
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.069737
  8. Sci Rep. 2025 Jul 01. 15(1): 22379
      The pathogenesis of myocardial ischemia-reperfusion injury (MIRI) is not fully clear. This study aims to investigate the role of mitochondrial-associated endoplasmic reticulum membrane (MAM)-related calcium overload in mitophagy. In vitro and in vivo models were established to simulate MIRI. Cellular injury, apoptosis and mitophagy were measured and gene expression was analysized. The expression levels of glucose-regulated protein 75 (GRP75), receptor for inositol 1,4,5-trisphosphate (IP3R3), voltage-dependent anion-selective channel 1 (VDAC1), and calmodulin (CaM) and the mitochondrial calcium content, mitophagy and apoptosis were significantly increased in MIRI or hypoxia/reoxygenation (H/R) cells when compared to controls, but the mitochondrial membrane potential and ATP significantly decreased. GRP75 knockdown significantly inhibited CaM expression, mitochondrial calcium overload and mitophagy of H9C2 cells, whereas had no significant effect on IP3R3 and VDAC1 expression. CaM knockdown had no significant effect on the expression of GRP75, IP3R3 and VDAC1, and on mitochondrial calcium concentration, ATP levels and mitochondrial membrane potential of H9C2 cells, but significantly inhibited mitophagy and apoptosis. Collectively, these data suggest that the IP3R3-GRP75-VDAC1/CaM axis plays an important role in mitochondrial autophagy injury during myocardial ischemia-reperfusion and that it is a potential target for MIRI treatment.
    Keywords:  CaM; IP3R3-GRP75-VDAC1 complex; Mitochondrial calcium overload; Mitophagy; Myocardial ischemia reperfusion injury (MIRI)
    DOI:  https://doi.org/10.1038/s41598-025-07977-5
  9. Apoptosis. 2025 Jul 01.
      Herpes simplex virus type 1 (HSV-1), a neurotropic virus, hijacks the critical neuronal organelle-mitochondria-to establish lifelong latent infection and potentially accelerate neurodegenerative pathologies. Research indicates that HSV-1 infection disrupts mitochondrial dynamics, impairs its bioenergetic function, and compromises interorganellar communication. This disruption is primarily achieved through the degradation of mitochondrial DNA (mtDNA) and the functional alteration of key proteins, leading to excessive production of reactive oxygen species (ROS), intracellular calcium dysregulation, and abnormal energy metabolism. These alterations not only diminish cellular energy production and exacerbate oxidative damage but also readily trigger neuronal cell death. Crucially, the virus specifically interferes with mitochondrial-endoplasmic reticulum contact sites (MERCs) to evade immune surveillance while simultaneously promoting its own replication. In severe encephalitis, mitochondrial damage is closely associated with neuroinflammation. For Alzheimer's disease (AD), HSV-1 may synergize with amyloid-beta pathology through ROS and viral proteins (such as glycoprotein B (gB) and glycoprotein I (gI)), exacerbating disease progression. Paradoxically, HSV-1 also inhibits immediate cell death to sustain host cell survival, facilitating latent viral reactivation. Research elucidating how the virus exploits mitochondria for pathogenesis suggests that future therapeutic strategies could combine classical antiviral drugs with agents that protect mitochondrial function (e.g., antioxidants). This combined approach holds promise for combating acute infection and potentially mitigating the progression of associated neurodegenerative diseases.
    Keywords:  AD; HSE; HSV-1; Immune evasion; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s10495-025-02142-9
  10. Sci Rep. 2025 Jul 01. 15(1): 22054
      Triple-negative breast cancer (TNBC) is a particularly aggressive and metastatic subtype, characterized by the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Outcomes for TNBC patients vary widely, suggesting this classification encompasses different cancers with distinct histological, genomic, and immunological profiles, leading to variable prognoses. The tumor microenvironment, particularly the expression and localization of promyelocytic leukemia protein (PML) in tumor-associated macrophages (TAMs), can influence patient outcomes by modulating inflammation. The beneficial prognostic role of increased tumor-infiltrating lymphocytes (TILs) in TNBC is well-established. In this retrospective study, we found that PML expression in tumor cells is inversely related to the presence of TILs and is associated with poorer outcomes. Patients with disease recurrence exhibited higher levels of TAMs with predominantly nuclear-localized PML, in contrast to patients who showed complete recovery. The accumulation of PML in the nucleus reduces its presence at ER-mitochondria contact sites, impairing its interaction with the NLRP3 inflammasome and leading to increased IL-1β secretion. This promotes a pro-inflammatory tumor microenvironment as seen in patients with adverse outcomes. Our findings suggest that both PML expression in cancer cells and its localization in TAMs can serve as additional prognostic factors, highlighting the potential of PML as a therapeutic target in TNBC.
    Keywords:  Breast cancer; PML; Prognostic markers; Triple negative breast cancer; Tumor-associated macrophages; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1038/s41598-025-01671-2